More than 99% of cervical cancers have been associated with human papillomaviruses (HPVs), particularly HPV-16. HPV-associated cervical malignancies might be prevented or treated by induction of the appropriate virus-specific immune responses in patients. HPV-associated cervical malignancies might be prevented or treated by induction of the appropriate virus-specific immune responses in patients. The overall objective of the multi-disciplinary research program is to identify relevant immunological mechanisms that mediate beneficial clinical outcomes of vaccination. The working hypotheses are that 1) testing a 'pipeline' of novel HPV vaccines will generate measurable clinical, pathological, and virological outcomes, and 2) immunological parameters that significantly correlate with thee outcomes can serve as predictors of vaccine effects and provide insight into relevant mechanisms of immunity. The HPV vaccine trials undergoing at the Johns Hopkins Hospital (JHH) provide a unique opportunity for us to identify the most potent HPV vaccine(s) and the immunological parameters that are most relevant to these vaccine effects. The sera, peripheral blood mononuclear cells, biopsy materials from these HPV vaccine trials at JHH are invaluable to the development and characterization of important immunological parameters. Dr. Roden (Project 1) will characterize protective humoral immune responses generated by patients vaccinated with HPV-16 virus-like particles (VLP) and HPV-16 chimeric HPV L1/L2-E2-E7 VLP. Dr. Wu (Project 2) and Dr. Pardoll (Project 3) will develop several new in vitro and in vivo HPV- specific cellular immunological assays and characterize the cell-mediated immune responses generated by multiple E7-specific HPV vaccines. The projects will cooperatively identify the relevant immunological assays that correlate with clinical, virological and pathological indicators in humans. A strong correlation between relevant immunological parameters and clinical/virological outcomes will provide insight into how the host develops and effects protective immune responses as a result of vaccination, help establish criteria for the evaluation of newer generations of vaccines, and provide a foundation for the rational development of new vaccines.